期刊论文详细信息
BMC Biology
Widespread amyloidogenicity potential of multiple myeloma patient-derived immunoglobulin light chains
Research Article
Sabine Metzger1  Jan Hansen2  Stefan U. Egelhaaf2  Florian Platten3  Rasmus K. Norrild4  Paolo Marcatili5  Magnus Haraldson Høie5  Amelie Boquoi6  Rainer Haas6  Roland Fenk6  Florian Tucholski7  Rebecca Sternke-Hoffmann8  Alexander K. Buell9  Luitgard Nagel-Steger1,10  Thomas Pauly1,10  Christian Malosse1,11  Magalie Duchateau1,11  Martial Rey1,11  Mathieu Dupré1,11  Julia Chamot-Rooke1,11 
[1] Cologne Biocenter, Cluster of Excellence on Plant Sciences, Mass Spectrometry Platform, University of Cologne, Cologne, Germany;Condensed Matter Physics Laboratory, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany;Condensed Matter Physics Laboratory, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany;Forschungszentrum Jülich GmbH, IBI-4, Jülich, Germany;Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark;Department of Health Technology, Technical University of Denmark, Lyngby, Denmark;Department of Hematology, Oncology and Clinical Oncology, Heinrich-Heine Universität Düsseldorf, Düsseldorf, Germany;Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany;Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany;Department of Biology and Chemistry, Paul Scherrer Institute, Villigen, Switzerland;Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany;Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark;Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany;Forschungszentrum Jülich GmbH, IBI-7, Jülich, Germany;Mass Spectrometry for Biology Unit, CNRS USR2000, Institut Pasteur, 75015, Paris, France;
关键词: Amyloid;    Immunoglobulin;    Multiple myeloma;    AL amyloidosis;    Light chain;    Multiparametric approach;   
DOI  :  10.1186/s12915-022-01506-w
 received in 2022-06-22, accepted in 2022-12-15,  发布年份 2022
来源: Springer
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【 摘 要 】

BackgroundIn a range of human disorders such as multiple myeloma (MM), immunoglobulin light chains (IgLCs) can be produced at very high concentrations. This can lead to pathological aggregation and deposition of IgLCs in different tissues, which in turn leads to severe and potentially fatal organ damage. However, IgLCs can also be highly soluble and non-toxic. It is generally thought that the cause for this differential solubility behaviour is solely found within the IgLC amino acid sequences, and a variety of individual sequence-related biophysical properties (e.g. thermal stability, dimerisation) have been proposed in different studies as major determinants of the aggregation in vivo. Here, we investigate biophysical properties underlying IgLC amyloidogenicity.ResultsWe introduce a novel and systematic workflow, Thermodynamic and Aggregation Fingerprinting (ThAgg-Fip), for detailed biophysical characterisation, and apply it to nine different MM patient-derived IgLCs. Our set of pathogenic IgLCs spans the entire range of values in those parameters previously proposed to define in vivo amyloidogenicity; however, none actually forms amyloid in patients. Even more surprisingly, we were able to show that all our IgLCs are able to form amyloid fibrils readily in vitro under the influence of proteolytic cleavage by co-purified cathepsins.ConclusionsWe show that (I) in vivo aggregation behaviour is unlikely to be mechanistically linked to any single biophysical or biochemical parameter and (II) amyloidogenic potential is widespread in IgLC sequences and is not confined to those sequences that form amyloid fibrils in patients. Our findings suggest that protein sequence, environmental conditions and presence and action of proteases all determine the ability of light chains to form amyloid fibrils in patients.

【 授权许可】

CC BY   
© The Author(s) 2023

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